Blood-brain barrier, ion homeostasis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms

The finding that epileptic seizures alter blood-brain barrier (BBB) propert ies has stimulated interest into the possibility that phenotypic changes in brain endothelium may constitute a pathological initiator leading to seizu res. Recent evidence obtained from epileptic patients undergoing cortical r esection, demonstrated abnormal expression of glucose transporter molecules (GLUT1), while [F-18]deoxyglucose PET studies demonstrated regions of decr eased glucose uptake and hypometabolism in seizure foci. The properties of other 'nonexcitable CNS cells' are also altered in epileptic tissue, and gl ial cells from epileptic brain displayed diminished capacity for ionic home ostasis; voltage-dependent mechanisms were primarily affected, increasing r eliance on energy-dependent mechanisms. Diminished ion homeostasis together with increased metabolic demand of hyperactive neurons may further aggrava te the neuropathological consequences of BBB loss of glucose uptake mechani sms. Since ketone bodies can provide an alternative to glucose to support b rain energy requirements, it is hypothesized that one of the mechanisms of the ketogenic diet in epilepsy may relate to increased availability of beta -hydroxybutyrate, a ketone body readily transported at the BBB. This hypoth esis is supported by the fact that the ketogenic diet is the treatment of c hoice for the glucose transporter protein syndrome and pyruvate dehydrogena se deficiency, both associated with cerebral energy failure and seizures. ( C) 1999 Elsevier Science B.V. All rights reserved.